Elucidating the molecular basis of regulatory T cell differentiation and function

2010 Fiscal Year Final Research Report

• Project/Area Number: 20689012
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Immunology
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: HORI Shohei The Institute of Physical and Chemical Research, 免疫恒常性研究ユニット, ユニットリーダー (50392113)
• Project Period (FY): 2008 – 2010
• Keywords: 自己免疫疾患 / 免疫寛容 / 免疫制御 / 制御性T細胞 / 遺伝子発現制御 / 分化可塑性

Research Abstract

We conducted two lines of research, which aim at elucidating the mechanisms of regulatory T cell (Treg) differentiation and function. First, we asked whether and how naturally occurring Foxp3 gene mutations identified in human IPEX affect Treg differentiation and function by generating knock-in mice. We found that one of the mutations resulted in the development of autoimmune diseases similar to human IPEX, which was associated with a selective deficiency of a "tissue-seeking" subset of Treg cells. These results suggest that Foxp3+ Treg cells consist of functionally distinct subsets, each of which may play non-redundant roles in the establishment and maintenance of self-tolerance. Second, we found that Foxp3^+ T cells are heterogeneous in that they contain a minor, functionally uncommitted, plastic subpopulation that loses Foxp3 expression and converts to helper T cells in response to environmental perturbations.

Research Products

• [Journal Article] Enhanced murine contact hypersensitivity by depletion of endogenous regulatory T cells in the sensitization phase. (2011)
  • Author(s): Honda, T., Otsuka, A., Tanizaki, H., Minegaki, Y., Nagao, K., Waldmann, H., Tomura, M., Hori, S., Miyachi, Y., Kabashima, K.
  • Journal Title: J.Dermatol.Sci. 61 Pages: 144-147
  • Peer Reviewed
• [Journal Article] Induction of colonic regulatory T cells by indigenous Clostridium species. (2011)
  • Author(s): Atarashi, K., Tanoue, T., Shima, T., Imaoka, A., Kuwahara, T., Momose, Y., Cheng, G., Yamasaki, S., Saito, T., Ohba, Y., Taniguchi, T., Takeda, K., Hori, S., Ivanov, I.I., Umesaki, Y., Itoh, K., Honda, K.
  • Journal Title: Science 331 Pages: 337-341
  • Peer Reviewed
• [Journal Article] Developmental plasticity of Foxp3^+ regulatory T cells. (2010)
  • Author(s): Hori, S.
  • Journal Title: Curr.Opin.Immunol.y 22 Pages: 575-582
  • Peer Reviewed
• [Journal Article] Activated regulatory T cells are the major T cell type emigrating from sensitized skin. (2010)
  • Author(s): Tomura, M., Honda, T., Tanizaki, H., Otsuka, A., Egawa, G., Tokura, Y., Waldmann, H., Hori, S., Cyster, J.G., Watanabe, T., Miyachi, Y., Kanagawa, O., Kabashima, K.
  • Journal Title: J.Clin.Invest. 120 Pages: 883-893
  • Peer Reviewed
• [Journal Article] Exacerbation of delayed-type hypersensitivity responses in EBV-induced gene-3 (EBI-3)-deficient mice. (2010)
  • Author(s): Tong, H., Miyazaki, Y., Yamazaki, M., Hara, H., Waldmann, H., Hori, S., Yoshida, H.
  • Journal Title: Immunol.Lett. 128 Pages: 108-115
  • Peer Reviewed
• [Journal Article] c-Rel : A pioneer in directing regulatory T cell lineage commitment? (2010)
  • Author(s): Hori, S.
  • Journal Title: Eur.J.Immunol. 40 Pages: 664-667
  • Peer Reviewed
• [Journal Article] Cutting Edge : Depletion of Foxp3+ cells leads to induction of autoimmunity by specific ablation of regulatory T cells in genetically targeted mice. (2009)
  • Author(s): Kim, J., Lahl, K., Hori, S., Loddenkemper, C., Chaudhry A., deRoos, P., Rudensky, A., Sparwasser, T.
  • Journal Title: J.Immunol. 183 Pages: 7631-7634
  • Peer Reviewed
• [Journal Article] Preferential generation of follicular B helper T cells from Foxp3^+ T cells in gut Peyer's patches. (2009)
  • Author(s): Tsuji, M., Komatsu, N., Kawamoto, S., Kanagawa, O., Honjo, T., Hori, S., Fagarasan, S.
  • Journal Title: Science 323 Pages: 1488-1492
  • Peer Reviewed
• [Journal Article] Heterogeneity of natural Foxp3^+ T cells : a committed regulatory T cell lineage and an uncommitted minor population retaining plasticity. (2009)
  • Author(s): Komatsu, N., Mariotti-Ferrandiz, M.E., Wang, Y., Malissen, B., Waldmann, H., Hori, S.
  • Journal Title: PNAS 106 Pages: 1903-1908
  • Peer Reviewed
• [Journal Article] Protection of IFN-γ signaling deficient NOD mice from diabetes by cyclophosphamide. (2008)
  • Author(s): Mori, Y., Kato, T., Kodaka, T., Kanagawa E.M., Hori, S., Kanagawa, O.
  • Journal Title: Int.Immunol. 20 Pages: 1231-1237
  • Peer Reviewed
• [Journal Article] Foxp3 inhibits RORγt-mediated IL-17A mRNA transcription through direct interaction with RORγt. (2008)
  • Author(s): Ichiyama, K., Yoshida, H., Wakabayashi, Y., Chinen, T., Saeki, K., Nakaya, M., Takasu, G., Hori, S., Yoshimura, A., Kobayashi, T.
  • Journal Title: J.Biol.Chem. 283 Pages: 17003-17008
  • Peer Reviewed
• [Journal Article] Rethinking the molecular definition of regulatory T cells. (2008)
  • Author(s): Hori, S.
  • Journal Title: Eur.J.Immunol. 38 Pages: 928-930
  • Peer Reviewed
• [Presentation] Stability and plasticity in regulatory T cell differentiation (2010)
  • Author(s): Hori, S
  • Organizer: The 14^<th> International Congress of Immunology
  • Place of Presentation: 神戸
  • Year and Date: 20100822-20100827
• [Presentation] Stability and plasticity in regulatory T cell differentiation (2010)
  • Author(s): Hori, S
  • Organizer: Keystone Symposia "Tolerance and Autoimmunity"
  • Place of Presentation: Taos, New Mexico, USA
  • Year and Date: 20100221-20100226
• [Presentation] Robustness and plasticity in regulatory T cell differentiation (2009)
  • Author(s): Hori, S
  • Organizer: The 39^<th> Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: 大阪
  • Year and Date: 20091202-20091204
• [Presentation] Lineage stability and plasticity in regulatory T cell differentiation (2009)
  • Author(s): Hori, S
  • Organizer: The 12^<th> US-Japan Cellular and Gene Therapy Conference "Immune Regulation"
  • Place of Presentation: Bethesda, Maryland, USA
  • Year and Date: 2009-02-26
• [Presentation] Dissecting Foxp3-dependent molecular program of regulatory T cell differentiation and function (2008)
  • Author(s): Hori, S
  • Organizer: BMB2008
  • Place of Presentation: 神戸
  • Year and Date: 20081209-20081212
• [Presentation] Foxp3 and its essential function for T cell regulation (2008)
  • Author(s): Hori, S
  • Organizer: International Symposium "Frontiers in Allergy and Autoimmunity"
  • Place of Presentation: Mainz, Germany
  • Year and Date: 20080530-20080531
• [Remarks] ホームページ
  • URL: http://www.riken.jp/r-world/research/lab/rcai/home/index.html